Cost-effectiveness of a patient-centred approach to managing multimorbidity in primary care:a pragmatic cluster randomised controlled trial

Objective Patients with multiple chronic health conditions are often managed in a disjointed fashion in primary care, with annual review clinic appointments offered separately for each condition. This study aimed to determine the cost-effectiveness of the 3D intervention, which was developed to improve the system of care. Design Economic evaluation conducted alongside a pragmatic cluster-randomised trial. Setting General practices in three centres in England and Scotland. Participants 797 adults with three or more chronic conditions were randomised to the 3D intervention, while 749 participants were randomised to receive usual care. Intervention The 3D approach: comprehensive 6-monthly general practitioner consultations, supported by medication reviews and nurse appointments. Primary and secondary outcome measures The primary economic evaluation assessed the cost per quality-adjusted life year (QALY) gained from the perspective of the National Health Service (NHS) and personal social services (PSS). Costs were related to changes in a range of secondary outcomes (QALYs accrued by both participants and carers, and deaths) in a cost-consequences analysis from the perspectives of the NHS/PSS, patients/carers and productivity losses. Results Very small increases were found in both QALYs (adjusted mean difference 0.007 (-0.009 to 0.023)) and costs (adjusted mean difference 126 pound (-739 pound to 991)) pound in the intervention arm compared with usual care after 15 months. The incremental cost-effectiveness ratio was 18 pound 499, with a 50.8% chance of being cost-effective at a willingness-to-pay threshold of 20 pound 000 per QALY (55.8% at 30 pound 000 per QALY). Conclusions The small differences in costs and outcomes were consistent with chance, and the uncertainty was substantial; therefore, the evidence for the cost-effectiveness of the 3D approach from the NHS/PSS perspective should be considered equivocal

Identification of key structural elements for neuronal calcium sensor-1 function in the regulation of the temperature-dependency of locomotion in C. elegans

BACKGROUND: Intracellular Ca(2+) regulates many aspects of neuronal function through Ca(2+) binding to EF hand-containing Ca(2+) sensors that in turn bind target proteins to regulate their function. Amongst the sensors are the neuronal calcium sensor (NCS) family of proteins that are involved in multiple neuronal signalling pathways. Each NCS protein has specific and overlapping targets and physiological functions and specificity is likely to be determined by structural features within the proteins. Common to the NCS proteins is the exposure of a hydrophobic groove, allowing target binding in the Ca(2+)-loaded form. Structural analysis of NCS protein complexes with target peptides has indicated common and distinct aspects of target protein interaction. Two key differences between NCS proteins are the size of the hydrophobic groove that is exposed for interaction and the role of their non-conserved C-terminal tails. RESULTS: We characterised the role of NCS-1 in a temperature-dependent locomotion assay in C. elegans and identified a distinct phenotype in the ncs-1 null in which the worms do not show reduced locomotion at actually elevated temperature. Using rescue of this phenotype we showed that NCS-1 functions in AIY neurons. Structure/function analysis introducing single or double mutations within the hydrophobic groove based on information from characterised target complexes established that both N- and C-terminal pockets of the groove are functionally important and that deletion of the C-terminal tail of NCS-1 did not impair its ability to rescue. CONCLUSIONS: The current work has allowed physiological assessment of suggestions from structural studies on the key structural features that underlie the interaction of NCS-1 with its target proteins. The results are consistent with the notion that full length of the hydrophobic groove is required for the regulatory interactions underlying NCS-1 function whereas the C-terminal tail of NCS-1 is not essential. This has allowed discrimination between two potential modes of interaction of NCS-1 with its targets

Identification of key structural elements for neuronal calcium sensor-1 function in the regulation of the temperature-dependency of locomotion in C. elegans

BACKGROUND: Intracellular Ca2+ regulates many aspects of neuronal function through Ca2+ binding to EF hand-containing Ca2+ sensors that in turn bind target proteins to regulate their function. Amongst the sensors are the neuronal calcium sensor (NCS) family of proteins that are involved in multiple neuronal signalling pathways. Each NCS protein has specific and overlapping targets and physiological functions and specificity is likely to be determined by structural features within the proteins. Common to the NCS proteins is the exposure of a hydrophobic groove, allowing target binding in the Ca2+-loaded form. Structural analysis of NCS protein complexes with target peptides has indicated common and distinct aspects of target protein interaction. Two key differences between NCS proteins are the size of the hydrophobic groove that is exposed for interaction and the role of their non-conserved C-terminal tails. RESULTS: We characterised the role of NCS-1 in a temperature-dependent locomotion assay in C. elegans and identified a distinct phenotype in the ncs-1 null in which the worms do not show reduced locomotion at actually elevated temperature. Using rescue of this phenotype we showed that NCS-1 functions in AIY neurons. Structure/function analysis introducing single or double mutations within the hydrophobic groove based on information from characterised target complexes established that both N- and C-terminal pockets of the groove are functionally important and that deletion of the C-terminal tail of NCS-1 did not impair its ability to rescue. CONCLUSIONS: The current work has allowed physiological assessment of suggestions from structural studies on the key structural features that underlie the interaction of NCS-1 with its target proteins. The results are consistent with the notion that full length of the hydrophobic groove is required for the regulatory interactions underlying NCS-1 function whereas the C-terminal tail of NCS-1 is not essential. This has allowed discrimination between two potential modes of interaction of NCS-1 with its targets

Culex tarsalis is a competent vector species for Cache Valley virus

Background: Cache Valley virus (CVV) is a mosquito-borne orthobunyavirus endemic in North America. The virus is an important agricultural pathogen leading to abortion and embryonic lethality in ruminant species, especially sheep. The importance of CVV in human public health has recently increased because of the report of severe neurotropic diseases. However, mosquito species responsible for transmission of the virus to humans remain to be determined. In this study, vector competence of three Culex species mosquitoes of public health importance, Culex pipiens, Cx. tarsalis and Cx. quinquefasciatus, was determined in order to identify potential bridge vector species responsible for the transmission of CVV from viremic vertebrate hosts to humans. Results: Variation of susceptibility to CVV was observed among selected Culex species mosquitoes tested in this study. Per os infection resulted in the establishment of infection and dissemination in Culex tarsalis, whereas Cx. pipiens and Cx. quinquefasciatus were highly refractory to CVV. Detection of viral RNA in saliva collected from infected Cx. tarsalis provided evidence supporting its role as a competent vector. Conclusions: Our study provided further understanding of the transmission cycles of CVV and identifies Cx. tarsalis as a competent vector

Radionuclide Contaminant Burdens in Arctic Marine Mammals Harvested During Subsistence Hunting

We conducted gamma spectrometric analyses on more than 200 arctic marine mammal tissue samples. These samples were primarily provided by subsistence hunters from northern Alaska, with a smaller number of samples from the Resolute region in Canada. The majority of samples (>90%) had detectable levels of the anthropogenic radionuclide 137Cs, with a mean level observed in all samples of 0.67 Bq/kg dry weight ± 0.81 (SD). Converted to wet weight, the mean was 0.21 Bq/kg ± 0.19 SD. The median activity observed was 0.45 Bq/kg dry weight (0.18 Bq/kg wet weight) with a range from detection limits to 6.7 Bq/kg dry weight (1.1 Bq/kg wet weight). These findings confirm expectations that current anthropogenic gamma emitter burdens in marine mammals used in the North American Arctic as subsistence food resources are well below activities that would normally merit public health concern (~1000 Bq/kg wet weight). Some differences among species and tissues were observed. Beluga tissues had slightly higher mean burdens of 137Cs overall, and epidermis and muscle tissues in bowhead and beluga whales typically had higher burdens than other tissues analyzed. Low levels of the neutron activation product 108mAg (half-life 418 yr.), probably bioaccumulated from bomb fallout sources, were observed in 16 of 17 beluga livers analyzed, but were not found in any other tissues of beluga or in any other species sampled. A subset of 39 samples of various tissues was analyzed for the alpha and beta emitters 239,240Pu and 90Sr. Plutonium levels were near the threshold of detectability (~0.1 Bq/kg dry weight) in 6 of the 39 samples; all other samples had no detectable plutonium. A detectable level of 90Sr (10.3 ± 1.0 Bq/kg dry weight) was observed in only one of the 39 samples analyzed, a bowhead epidermis sample. Although the accumulation of 108mAg has not been previously reported in any marine mammal livers, all of our analytical measurements indicate that only very low levels of anthropogenic radioactivity are associated with marine mammals harvested and consumed in the North American Arctic.On a effectué des analyses gamma-spectrométriques sur plus de 200 échantillons de tissus prélevés sur des mammifères marins. La plupart de ces échantillons étaient fournis par des chasseurs de subsistance de l'Alaska septentrional, et un petit nombre venaient de la région de Resolute au Canada. La majorité des échantillons (> 90 p. cent) contenaient des niveaux détectables du radionucléide anthropique 137Cs, avec un niveau moyen observé dans tous les échantillons de 0,67 Bq/kg de poids sec ± 0,81 (écart-type). Convertie en poids frais, la moyenne était de 0,21 Bq/kg ± 0,19 d'écart-type. L'activité médiane observée était de 0,45 Bq/kg de poids sec (0,18 Bq/kg de poids frais) avec une fourchette allant des seuils de détection jusqu'à 6,7 Bq/kg de poids sec (1,1 Bq/kg de poids frais). Ces résultats confirment les réponses prévues, à savoir que les charges actuelles des émetteurs gamma anthropiques présentes chez les mammifères marins utilisés en Amérique du Nord comme ressource de subsistance sont bien inférieures aux niveaux qui voudraient normalement qu'on s'inquiète pour la santé publique (~1000 Bq/kg de poids frais). On a observé certaines différences dans les espèces et les tissus. Dans l'ensemble, les tissus prélevés sur le bélouga contenaient des charges moyennes de 137Cs légèrement plus élevées, et l'épiderme et les tissus musculaires de la baleine boréale et du bélouga avaient généralement des charges supérieures à celles trouvées dans les autres tissus analysés. Dans 16 des 17 foies de bélouga analysés, on a observé de faibles niveaux du produit d'activation neutronique 108mAg (demi-vie 418 années), dont la bioaccumulation est probablement due à des retombées de bombes atomiques, mais on n'en a observé aucune trace dans les autres tissus du bélouga ou de toute autre espèce échantillonnée. On a analysé un sous-ensemble de 39 échantillons provenant de tissus divers pour savoir s'ils contenaient des émetteurs alpha et bêta 239,240Pu et 90Sr. Dans 6 des 39 échantillons, les niveaux de plutonium étaient proches du seuil de détectabilité (~ 0,1 Bq/kg de poids sec), et on n'a pas trouvé de plutonium détectable dans aucun des autres échantillons. On a observé un niveau détectable de 90Sr (10,3 ± 1,0 Bq/kg de poids sec) dans un seul des 39 échantillons analysés, soit un échantillon d'épiderme de baleine boréale. Bien qu'on n'ait jamais rapporté auparavant une accumulation de 108mAg dans le foie d'un mammifère marin, toutes nos mesures analytiques révèlent que les mammifères marins faisant l'objet d'une activité d'exploitation et consommés dans l'Arctique nord-américain ne présentent que de très faibles niveaux de radioactivité anthropique

Selection on Coding and Regulatory Variation Maintains Individuality in Major Urinary Protein Scent Marks in Wild Mice

Recognition of individuals by scent is widespread across animal taxa. Though animals can often discriminate chemical blends based on many compounds, recent work shows that specific protein pheromones are necessary and sufficient for individual recognition via scent marks in mice. The genetic nature of individuality in scent marks (e.g. coding versus regulatory variation) and the evolutionary processes that maintain diversity are poorly understood. The individual signatures in scent marks of house mice are the protein products of a group of highly similar paralogs in the major urinary protein (Mup) gene family. Using the offspring of wild-caught mice, we examine individuality in the major urinary protein (MUP) scent marks at the DNA, RNA and protein levels. We show that individuality arises through a combination of variation at amino acid coding sites and differential transcription of central Mup genes across individuals, and we identify eSNPs in promoters. There is no evidence of post-transcriptional processes influencing phenotypic diversity as transcripts accurately predict the relative abundance of proteins in urine samples. The match between transcripts and urine samples taken six months earlier also emphasizes that the proportional relationships across central MUP isoforms in urine is stable. Balancing selection maintains coding variants at moderate frequencies, though pheromone diversity appears limited by interactions with vomeronasal receptors. We find that differential transcription of the central Mup paralogs within and between individuals significantly increases the individuality of pheromone blends. Balancing selection on gene regulation allows for increased individuality via combinatorial diversity in a limited number of pheromones

Non-renormalization of next-to-extremal correlators in N=4 SYM and the AdS/CFT correspondence

We show that next-to-extremal correlators of chiral primary operators in N=4 SYM theory do not receive quantum corrections to first order in perturbation theory. Furthermore we consider next-to-extremal correlators within AdS supergravity. Here the exchange diagrams contributing to these correlators yield results of the same free-field form as obtained within field theory. This suggests that quantum corrections vanish at strong coupling as well.Comment: 21 pages, LaTex, 9 eps figures, typos corrected and references adde